High-dose intravenous immunoglobulin (IVIg) is an effective treatment for many antibody-mediated neuromuscular diseases, suggesting that IVIg directly interferes with the pathways through which the pathogenic antibodies exert their effects. However, the precise mechanisms of action are unclear. Serum anti-GQ1b antibodies are strongly associated with ophthalmoplegia in patients with Miller Fisher syndrome (MFS) and Guillain-Barre syndrome (GBS). They induce complement-mediated alpha-latrotoxin-like effects on mouse neuromuscular junctions (NMJs) ex vivo, comprising transient muscle fibre twitching, due to a dramatic increase in the frequency of miniature end-plate potentials (spontaneous quantal acetylcholine release), followed by transmission block. To clarify the mechanisms by which IVIg may act in MFS and GBS, we investigated its effects on the interaction of anti-GQ1b antibodies with GQ1b in vitro and on anti-GQ1b antibody-mediated NMJ injury ex vivo, using anti-GQ1b-positive serum samples from MFS/GBS patients. We show that IVIg inhibits the binding of anti-GQ1b antibodies to GQ1b, thereby preventing complement activation and subsequent pathophysiological effects in our ex vivo mouse NMJ model. These results provide further support for the hypothesis that anti-ganglioside antibodies are the pathogenic factors in MFS/GBS and show that this NMJ model provides a suitable system for investigating the therapeutic effects of IVIg in antibody-mediated neuromuscular diseases.

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Keywords *Immunoglobulins, Intravenous, Antibodies/analysis/*metabolism, Biological Assay, Complement Activation, Complement C1q/analysis, Enzyme-Linked Immunosorbent Assay/methods, Gangliosides/*immunology, Guillain-Barre Syndrome/drug therapy/immunology, Humans, Immunoglobulin G/immunology, Miller Fisher Syndrome/drug therapy/immunology, Motor Neurons/*immunology, Muscle Contraction, Neuromuscular Diseases/*drug therapy/immunology, Neuromuscular Junction/*immunology, Research Support, Non-U.S. Gov't, Statistics, Nonparametric
Persistent URL dx.doi.org/10.1093/brain/awg235, hdl.handle.net/1765/13188
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Citation
Jacobs, B.C., O' Hanlon, G.M., Bullens, R.W., Veitch, J., Plomp, J.J., & Willison, H.J.. (2003). Immunoglobulins inhibit pathophysiological effects of anti-GQ1b-positive sera at motor nerve terminals through inhibition of antibody binding.. Brain: a journal of neurology, 126(10), 2220–2234. doi:10.1093/brain/awg235